桦木醇胺衍生物的合成

2021-04-27冯振李金莲申希峰韩荣弼

延边大学学报（自然科学版） 2021年1期

冯振, 李金莲, 申希峰, 韩荣弼

( 延边大学理学院，吉林延吉 133002 )

0 引言

桦木醇(betulin)又名白桦醇酯，是一种天然的羽扇豆烷型五环三萜类化合物，具有消炎[1-2]、抗HIV[3-5]、抗肿瘤[6-9]等功效.为了进一步开发和利用桦木醇，近年来学者们对桦木醇的结构开展了较多的修饰研究[10].H.Kommera等[11]研究发现，桦木酸的C-3羟基和桦木醇的C-28羟基接入氯乙酰后，其衍生物对10种癌细胞都显示出极大的活性.目前已有含胺基的化合物药物被应用到临床中，用于治疗癌症、抑郁等[12-16].黄骏凯等[17]研究发现，在大黄酸中引入不同胺基合成的大黄酸衍生物，对人骨肉瘤细胞的抑制活性显著高于大黄酸.鉴于上述研究的启示，本文以桦木醇为起始物，用9种仲胺和二胺在其C-3、C-28 和C-30上进行修饰，合成了31种桦木醇胺衍生物，并利用1H-NMR、13C-NMR、MALDI-TOF-MS和FT-IR 对其结构进行了表征.

1 实验部分

1.1 主要仪器与试剂

傅立叶变换红外光谱仪,Shimadzu公司;300 MHz核磁共振仪,Bruker公司;飞行时间质谱仪,Shimadzu公司.氯乙酰氯、二氯甲烷、乙腈、吡啶、对二甲氨基吡啶、三苯基氯甲烷、无水碳酸钾、三氯甲烷、无水乙醇、甲醇、二胺、吡咯烷、哌啶、吗啉、哌嗪、二甲基甲酰胺、乙二醇二甲醚、四氢呋喃、四氯化碳、乙酸酐、硅胶(300～400目)、分子筛，国药集团化学试剂有限公司；氢化钙，天津市化学试剂研究所有限公司;无水硫酸镁、三乙胺、氢氧化钠、吡啶对甲苯磺酸盐、偶氮二异丁腈、N-溴代琥珀酰亚胺，天津市科密欧化学试剂有限公司；二氯甲烷和乙腈在氢化钙中回流，然后蒸馏并用分子筛保存备用.

1.2 合成方法

1.2.1系列化合物2、4、6的合成

桦木醇由桦树皮(来自长白山地区的白桦树)提取所得，桦木醇中间体1、3、5和7均来自韩荣弼课题组前期工作所得[18].将用精制乙腈溶解的中间体1、3、5和无水碳酸钾置于50 mL圆底烧瓶中，室温搅拌5 min后加入仲胺，并继续在室温下搅拌至反应物消失(或加入二胺，在80 ℃油浴下搅拌至反应物消失)；将产物用二氯甲烷或者乙酸乙酯溶解后水洗3次，然后用石油醚和乙酸乙酯体系或三氯甲烷和甲醇体系进行洗脱.系列化合物2、4、6的合成路线见图1.

图1 系列化合物2、4、6的合成路线

28-O-[2-(吡咯烷-1-基)乙酰基]-桦木醇(2a) 白色固体;Rf=0.49，V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 429,2 945,2 871,1 736,1 641,1 187,1 005,882;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.60(1H,s),4.35(1H,d,J=10.2 Hz),3.93(1H,d,J=10.2 Hz),3.40(2H,d,J=4.8 Hz),3.16～3.24(1H,m),2.70(4H,s),2.40～2.50(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z554[M+H]+.

28-O-[2-(哌啶-1-基)乙酰基]-桦木醇(2b) 白色固体;Rf=0.29，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 448,2 940,1 738,1 642,1 178,1 108,883;1H NMR(300 MHz,CDCl3):δ4.71(1H,s),4.70(1H,s),4.35(1H,d,J=10.5 Hz),3.91(1H,d,J=10.5 Hz),3.15～3.28(3H,m),2.38～2.64(5H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z568[M+H]+.

28-O-[2-(吗啉-4-基)乙酰基]-桦木醇(2c) 白色固体;Rf=0.27，V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 481,2 946,1 744,1 641,1 193,1 117,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.61(1H,s),4.37(1H,d,J=10.8 Hz),3.92(1H,d,J=10.8 Hz),3.72～3.84(4H,t,J=4.8 Hz),3.13～3.32(3H,m),2.61(4H,d,J=5.1 Hz),2.37～2.54(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.84(3H,s),0.77(3H,s);TOF-MS:m/z570[M+H]+.

28-O-[2-(哌嗪-1-基)乙酰基]-桦木醇(2d) 白色固体;Rf=0.23，V(乙酸乙酯)∶V(甲醇)=1∶1;IR(KBr,cm-1):3 238,2 941,1 748,1 642,1 183,1 157,880;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.60(1H,s),4.35(1H,d,J=10.8 Hz),3.91(1H,d,J=10.8 Hz),3.13～3.33(3H,m),2.95(4H,t,J=4.8 Hz),2.57(4H,d,J=2.1 Hz),2.38～2.52(1H,m),1.69(3H,s),1.26(3H,s),1.04(3H,s),0.98(3H,s),0.83(3H,s),0.77(3H,s);TOF-MS:m/z569[M+H]+.

28-O-(二甲氨基乙酰基)-桦木醇(2e) 无色液体;Rf=0.08，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.07,110.0,150.2,171.7,172.3.

28-O-(二乙氨基乙酰基)-桦木醇(2f) 无色液体;Rf=0.21，V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二丙氨基乙酰基)-桦木醇(2g) 无色液体;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=20∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二丁氨基乙酰基)-桦木醇(2h) 无色液体;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

28-O-(二戊氨基乙酰基)-桦木醇(2i) 无色液体;Rf=0.39,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(3H,s),0.87(6H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3,28-二-O-[2-(吡咯烷-1-基)乙酰基]-桦木醇(4a) 无色液体;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 949,1 745,1 641,1 182,1 158,881;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.52～4.68(2H,m),4.36(1H,d,J=11.1 Hz),3.92(1H,d,J=11.1 Hz),3.42(4H,d,J=3.9 Hz),2.74(8H,s),2.37～2.56(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.86(3H,s),0.84(3H,s);TOF-MS:m/z665[M+H]+.

3,28-二-O-[2-(哌啶-1-基)乙酰基]-桦木醇(4b) 无色液体;Rf=0.28,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 936,1 748,1 643,1 175,1 130,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.48～4.68(2H,m),4.36(1H,d,J=11.1 Hz),3.90(1H,d,J=11.1 Hz),3.21(4H,d,J=7.2 Hz),2.25～2.70(9H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.85(6H,s);TOF-MS:m/z693[M+H]+.

3,28-二-O-[2-(吗啉-4-基)乙酰基]-桦木醇(4c) 无色液体;Rf=0.23,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 949,1 745,1 641,1 192,1 117,868;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.50～4.64(2H,m),4.37(1H,d,J=11.1 Hz),3.90(1H,d,J=11.1 Hz),3.78(8H,t,J=3.9 Hz),3.25(4H,d,J=7.5 Hz),2.63(8H,d,J=3.3 Hz),2.38～2.52(1H,m),1.69(3H,s),1.27(3H,s),1.04(3H,s),0.98(3H,s),0.86(3H,s),0.85(3H,s);TOF-MS:m/z697[M+H]+.

3,28-二-O-[2-(哌嗪-1-基)乙酰基]-桦木醇(4d) 白色固体;Rf=0.18,V(三氯甲烷)∶V(甲醇)=5∶1;IR(KBr,cm-1):3 424,2 946,1 743,1 637,1 183,1 014,883;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.51～4.67(2H,m),4.37(1H,d,J=11.7 Hz),3.91(1H,d,J=11.7 Hz),3.23(4H,d,J=8.7 Hz),2.98(8H,s),2.61(8H,s,J=2.1 Hz),2.22～2.51(3H,m),1.70(3H,s),1.05(3H,s),0.99(3H,s),0.86(9H,s);TOF-MS:m/z695[M+H]+.

3,28-二-O-(二甲氨基乙酰基)-桦木醇(4e) 无色液体;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 945,1 742,1 641,1 456,1 389,1 196,1 103,883;1H NMR(300 MHz,CDCl3):δ4.66(1H,s),4.51～4.56(2H,m),4.31(1H,d,J=11.1 Hz),3.88(1H,d,J=11.1 Hz),4.11～4.23(4H,m),2.30～2.46(12H,m),1.68(3H,s),1.04(3H,s),0.94(3H,s),0.82(9H,s);13C NMR(75 MHz,CDCl3):δ14.8,16.0,16.2,16.6,18.2,19.1,20.8,23.8,25.2,27.1,28.0,29.6,29.8,34.1,34.7,37.1,37.6,37.8,38.4,41.0,42.8,45.3,45.4,46.5,47.8,48.8,50.3,55.3,60.4,60.5,62.9,81.1,110.0,150.1,170.6,171.2.

3,28-二-O-(二丙氨基乙酰基)-桦木醇(4g) 无色液体;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 955,1 730,1 643,1 460,1 383,1 180,1 096,978;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.59(1H,s),4.49～4.54(1H,m),4.30(1H,d,J=11.1 Hz),3.87(1H,d,J=11.1 Hz),3.28(4H,d,J=6.9 Hz),2.54(8H,t,J=7.8 Hz),2.39～2.48(1H,m),1.68(3H,s),1.03(3H,s),0.97(3H,s),0.90(6H,s),0.87(6H,s),0.85(9H,s);13C NMR(75 MHz,CDCl3):δ11.8,14.8,16.1,16.2,16.8,18.3,19.2,20.8,21.0,23.9,25.2,27.1,28.1,29.7,29.9,34.2,34.7,37.2,37.7,37.9,38.5,41.0,42.8,46.5,47.8,48.9,50.4,55.2,55.5,56.5,56.6,62.7,81.1,110.0,150.2,171.5,172.2.

3,28-二-O-(二丁氨基乙酰基)-桦木醇(4h) 无色液体;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 953,1 730,1 643,1 460,1 381,1 176,1 098,883;1H NMR(300 MHz,CDCl3):δ4.69(1H,s),4.59(1H,s),4.49～4.55(1H,m),4.30(1H,d,J=11.0 Hz),3.88(1H,d,J=11.0 Hz),3.33(4H,d,J=6.1 Hz),2.57(8H,t,J=7.8 Hz),2.40～2.49(1H,m),1.69(3H,s),1.03(3H,s),0.97(3H,s),0.88(3H,s),0.93(6H,s),0.90(6H,s),0.85(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.7,18.3,19.2,20.6,20.9,23.9,25.2,27.1,28.1,29.6,29.8,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.2,54.3,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.4.

3,28-二-O-(二戊氨基乙酰基)-桦木醇(4i)无色液体;Rf=0.22,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(m,1H),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-[2-(吡咯烷-1-基)乙酰基]-桦木醇(6a) 白色固体;Rf=0.25,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 404,2 941,1 743,1 639,1 184,1 104,879;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.51～4.65(2H,m),3.82(1H,d,J=10.2 Hz),3.26～3.44(3H,m),2.67(4H,s),2.33～2.49(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.87(6H,s);TOF-MS:m/z554[M+H]+.

3-O-[2-(哌啶-1-基)乙酰基]-桦木醇(6b)白色固体;Rf=0.30,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 454,2 941,1 744,1 639,1 185,1 104,880;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.47～4.65(2H,m),3.81(1H,d,J=10.8 Hz),3.35(1H,d,J=10.8 Hz),3.19(2H,d,J=1.2 Hz),2.53(4H,t,J=5.1 Hz),2.31～2.48(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z568[M+H]+.

3-O-[2-(吗啉-4-基)乙酰基]-桦木醇(6c)白色固体;Rf=0.28,V(石油醚)∶V(乙酸乙酯)=2∶1;IR(KBr,cm-1):3 448,2 941,1 743,1 635,1 196,1 117,898;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.47～4.66(2H,m),3.71～3.88(5H,m),3.35(1H,d,J=10.8 Hz),3.23(2H,s),2.63(4H,d,J=3.6 Hz),2.32～2.49(1H,m),1.70(3H,s),1.04(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z570[M+H]+.

3-O-[2-(哌嗪-1-基)乙酰基]-桦木醇(6d)白色固体;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=1∶1;IR(KBr,cm-1):3 436,2 940,1 739,1 644,1 192,1 029,881;1H NMR(300 MHz,CDCl3):δ4.70(1H,s),4.49～4.66(2H,m),3.80(1H,d,J=10.8 Hz),3.34(1H,d,J=10.8 Hz),3.21(2H,s),2.95(4H,t,J=4.2 Hz),2.58(4H,d,J=3.3 Hz),2.31～2.49(1H,m),1.70(3H,s),1.03(3H,s),0.99(3H,s),0.85(3H,s),0.86(6H,s);TOF-MS:m/z569[M+H]+.

3-O-(二甲氨基乙酰基)-桦木醇(6e) 无色液体;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

穿着夫妻的鞋子，走着朋友的步子，两人突然变得客气起来了，见面问好分别问候，相互恢复了删除的好友和朋友圈的资格。半月后，王树林回家陪儿子，顺便疏通了一下下水道，自然，当夜他就躺在了辛娜的床上。又半月，王树林要买车，喊了辛娜来参考。一周后，王树林开着新车去了辛娜的单位，辛娜不在，说是请假了，辛娜的同事说，你怎么做老公的，老婆请假都不知道，开啥子玩笑？窘得王树林一脸赤红。这不，几天后，辛娜打来电话，在办公室嘈杂的背景声中说，老公，下班别做饭了，我们出去吃。

3-O-(二乙氨基乙酰基)-桦木醇(6f) 无色液体;Rf=0.20,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H，s),1.02(3H，s),0.96(3H，s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二丙氨基乙酰基)-桦木醇(6g) 无色液体;Rf=0.08,V(石油醚)∶V(乙酸乙酯)=20∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二丁氨基乙酰基)-桦木醇(6h) 无色液体;Rf=0.21,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

3-O-(二戊氨基乙酰基)-桦木醇(6i) 无色液体;Rf=0.38,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 930,1 732,1 643,1 462,1 381,1 175,1 101,883;1H NMR(300 MHz,CDCl3):δ4.68(1H,s),4.58(1H,s),4.51～4.54(1H,m),4.29(1H,d,J=11.0 Hz),3.86(1H,d,J=11.0 Hz),3.32(4H,d,J=5.8 Hz),2.52～2.57(8H,m),2.43～2.48(1H,m),1.68(3H,s),1.02(3H,s),0.96(3H,s),0.89(3H,s),0.87(9H,s),0.83(6H,s);13C NMR(75 MHz,CDCl3):δ14.1,14.8,16.1,16.2,16.8,18.2,19.2,20.9,22.7,23.9,25.2,27.1,27.6,28.1,29.6,29.9,31.9,34.2,34.7,37.1,37.7,37.8,38.5,41.0,42.8,46.4,47.8,48.9,50.3,54.6,54.7,55.2,55.4,62.7,81.0,110.0,150.2,171.7,172.3.

1.2.2系列化合物9的合成

将用质量分数为2%的氢氧化钠甲醇溶液溶解的化合物8a-d置于圆底烧瓶中，回流搅拌至反应物消失；旋干溶剂后用二氯甲烷溶解，再用饱和氯化钠溶液洗有机层3～4次.化合物8a-d的合成路线见图2.

图2 系列化合物9的合成路线

3,28-二-O-乙酰-30-(1-吡咯烷基)桦木醇(8a) 白色固体;Rf=0.34,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 924,2 855,1 739,1 460,1 260,1 240,1 026;1H NMR(300 MHz,CDCl3):δ4.97(1H,s),4.79(1H,s),4.40～4.60(1H,m),4.27(1H,d,J=11.1 Hz),3.85(1H,d,J=11.1 Hz),2.72～3.01(2H,m),2.27～2.57(5H,m),2.09(3H,s)，2.06(3H,s),1.05(3H,s),0.99(3H,s),0.86(6H,s)，0.85(3H,s).

3,28-二-O-乙酰-30-(1-哌啶基)桦木醇(8b) 白色固体;Rf=0.62,V(石油醚)∶V(乙酸乙酯)=5∶1;IR(KBr,cm-1):2 923,2 854,1 738,1 462,1 261,1 243,1 027,885;1H NMR(300 MHz,CDCl3):δ5.04(1H,s),4.77(1H,s),4.37～4.56(1H,m),4.28(1H,d,J=11.1 Hz),3.84(1H,d,J=11.1 Hz),2.67～2.98(2H,m),2.21～2.54(5H,m),2.08(3H,s),2.06(3H,s),1.05(3H,s),0.98(3H,s),0.86(6H,s),0.85(3H,s).

3,28-二-O-乙酰-30-(4-吗啉基)桦木醇(8c) 白色固体;Rf=0.63,V(石油醚)∶V(丙酮)=2∶1;IR(KBr,cm-1):2 923,2 854,1 736,1 460,1 261,1 076,1 023;1H NMR(300 MHz,CDCl3):δ5.15(1H,s),4.84(1H,s),4.39～4.58(1H,m),4.28(1H,d,J=11.1 Hz),3.85(1H,d,J=11.1 Hz),3.62～3.79(4H,m),2.72～3.04(2H,m),2.21～2.63(5H,m),2.08(3H,s),2.06(3H,s),1.05(3H,s),) 0.98(3H,s),0.86(6H,s),0.85(3H,s).

N,N′-二-(3，28-二-O-乙酰-30-桦木醇基)哌嗪(8d) 白色固体;Rf=0.45,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):2 924,2 854,1 736,1 373,1 258,1 023;1H NMR(300 MHz,CDCl3):δ4.98(2H,s),4.79(2H,s),4.42～4.59(2H,m),4.27(2H,d,J=11.1 Hz),3.85(2H,d,J=11.1 Hz),2.71～2.99(4H,m),2.24～2.62(10H,m),2.09(6H,s),2.06(6H,s),1.05(6H,s),0.99(6H,s),0.86(12H,s),0.85(6H,s);TOF-MS:m/z1 134[M+H]+.

30-(1-吡咯烷基)桦木醇(9a) 白色固体;Rf=0.11,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 349,2 942,2 870,1 460,1 032;1H NMR(300 MHz,CDCl3):δ4.92(1H,s),4.90(1H,s),3.79(1H,d,J=10.8 Hz),3.35(1H,d,J=10.8 Hz),3.17～3.25(1H,m),2.93～2.97(2H,m);TOF-MS:m/z510[M+H]+.

30-(1-哌啶基)桦木醇(9b) 白色固体;Rf=0.51,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 411,2 938,2 867,1 458,1 033;1H NMR(300 MHz,CDCl3):δ4.88(1H,s),3.80(1H,d,J=11.1 Hz),3.34(1H,d,J=11.1 Hz),3.20(1H,m),2.88～3.19(1H,m),2.76～2.84(2H,m);TOF-MS:m/z526[M+H]+.

30-(4-吗啉基)桦木醇(9c) 白色固体;Rf=0.32,V(石油醚)∶V(丙酮)=2∶1;IR(KBr,cm-1):3 411,2 944,2 867,1 455,1 035;1H NMR(300 MHz,CDCl3):δ4.92(1H,s),4.90(1H,s),3.82(1H,d,J=10.8 Hz),3.34(1H,d,J=10.8 Hz),3.20(1H,m),2.80～2.94(2H,m);TOF-MS:m/z528[M+H]+.

N,N′-二-(30-桦木醇基)哌嗪(9d) 白色固体;Rf=0.29,V(石油醚)∶V(乙酸乙酯)=4∶1;IR(KBr,cm-1):3 395,2 941,2 871,1 457,1 039;1H NMR(300 MHz,CDCl3):δ4.91(2H,s),3.80(2H,d,J=11.1 Hz),3.22(2H,d,J=11.1 Hz),3.18～3.19(2H,m),2.94(4H,m);TOF-MS:m/z967[M+H]+.

2 结果与分析

图3 化合物2a的结构

用哌嗪对中间体7的30位进行修饰显示(合成路线如图2所示)，该反应的大部分取代发生在哌嗪的两个氮上，即主要产物为化合物8d.化合物8d结构如图4所示.由化合物8d的1H-NMR谱中的几组氢信号(δ4.98、4.79、4.27、3.85、2.71～2.99、1.05、0.99、0.86、0.85)可知，化合物8d中存在桦木醇骨架.再由化合物8d的1H-NMR谱中哌嗪的C-1′亚甲基氢信号(δ2.24～2.62)，化合物8d的FT-IR谱中的羰基(1 736 cm-1)、酯碳氧键(1 258 cm-1)、碳氮键(1 373 cm-1)振动吸收峰，化合物8d的MALDI-TOF-MS谱中的m/z1 134分子离子峰，以及化合物8d与桦木醇Rf值的差异等可证实反应生成的是N,N′-二-(3，28-二-O-乙酰-30-桦木醇基)哌嗪.本文所合成的其他29个桦木醇胺衍生物经1H-NMR、13C-NMR、FT-IR 和MALDI-TOF-MS综合解析确认，其结构也是均基于桦木醇骨架生成的.

图4 化合物8d的结构

在合成化合物4a-c的过程中，在室温(25 ℃)下当以化合物3和K2CO3的摩尔比为1∶2，反应溶剂为二氯甲烷时，化合物4a的产率为67%，化合物4b的产率为65%，化合物4c的产率为70%.上述条件下未有化合物4d生成.当反应温度为80 ℃，化合物3和K2CO3的摩尔比不变，而改变反应溶剂时，反应有化合物4d生成，且其产率随溶剂的不同而不同.其中：以二氯甲烷作为溶剂时，化合物4d的产率为24%；以二甲基甲酰胺作为溶剂时，化合物4d的产率为33%；以乙二醇二甲醚作为溶剂时，化合物4d的产率为34%；以乙腈作为溶剂时，化合物4d的产率为47%；以四氢呋喃作为溶剂时，化合物4d的产率为35%；以四氯化碳作为溶剂时，化合物4d的产率为30%.表1为反应物间的不同摩尔比对产率的影响.由表1可以看出，中间体化合物3、K2CO3、哌嗪间的不同摩尔比对化合物4d的产率具有很大影响，其中中间体化合物3、K2CO3、哌嗪的摩尔比为1∶4∶10，反应溶剂为乙腈时，化合物4d的产率最高(68%).在中间体化合物1和5与哌嗪的实验中，中间体与K2CO3、哌嗪的最佳摩尔比为1∶2∶5.